Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy

NCT06470880 | Not Yet Recruiting Phase 2

• 1 other identifier: CFTSp175
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this clinical trial is to investigate adaptive therapy in late-stage cutaneous melanoma. The main question it aims to answer are: If the patient having breaks in their treatment allows the less resistant cells to continue to grow, this would result in a tumour with a lower proportion of resistant cells, making the tumour less resistant to the treatment, an increasing the time it takes for the disease to progress? Participants will

• Receive their allocated treatment regimen until their cancer progresses, they or their doctor withdraw them from the study, or until the study ends, whichever happens first.
• Attend fortnightly visits to hospital.
• Complete EORTC QLQ-C30 and PRO-CTCAE questionnaires, prior to treatment, every 12 weeks and at the point of cancer progression, to assess quality of life. Researchers will compare the adaptive therapy participant arm with a standard of care arm to answer the research question described above.

Conditions

Melanoma

Keywords

Adaptive Therapy

Outcome Measures

Primary Outcomes (1)

• To measure tumour response to re-introduction of encorafenib plus binimetinib following the first "drug off " period.

  Specific measure: Maximal reduction in percentage ctDNA mutant BRAF copies/ml of plasma from baseline 2 TAB level upon restart of E+B following first drug off period.

  3 years (Longitudinally throughout the study)

Secondary Outcomes (12)

• To measure the thresholds of percentage reduction in TAB level in ctDNA as a measure of response to stop drugs and the percentage increase in TAB as a decision to restart drugs.

  3 years (Longitudinally throughout the study)

• To measure maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) to therapy in Arm A vs. Arm B

  Randomisation until RECIST progression/clinical deterioration (estimated 12 months)

• To measure progression free survival (PFS) in Arm A vs. Arm B

  3 years (Continuously throughout the study)

• To measure time to clinical deterioration in Arm A vs. Arm B.

  3 years (Continuously throughout the study)

• To measure overall survival in Arm A vs. Arm B

  3 years (Continuously throughout the study)

Study Arms (2)

ARM A: Standard of care

ACTIVE COMPARATOR

Continuous dosing of encorafenib 450mg once daily plus binimetinib 45mg twice daily.

Drug: Standard of Care

ARM B: Adaptive therapy

EXPERIMENTAL

4 weeks of encorafenib 450mg once daily plus binimetinib 45mg twice daily, followed by adaptive cycles based on ctDNA TAB level

Drug: Adaptive Therapy

Interventions

Adaptive Therapy DRUG

A blood test that measures the amount of tumour DNA circulating in the patient's blood (known as ctDNA) will be conducted every two weeks to check if the cancer cells are still present, and if they are becoming active. The result of this test will allow doctors to monitor the activity of the tumour and judge when to pause and resume encorafenib and binimetinib treatment. This intermittent treatment is called 'adaptive therapy'.

ARM B: Adaptive therapy

Standard of Care DRUG

Encorafenib and binimetinib delivered to UK standard of care.

ARM A: Standard of care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At Screening
• Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study
• Histological confirmation of cutaneous melanoma
• ≥ 18 years of age
• Stage III un-resectable/ IV disease
• Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)
• BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)
• ECOG performance status 0/1/2
• Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs
• Adequate organ function as defined below:
• i. Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min
• Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B).
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B).
• At randomisation:

You may not qualify if:

• Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)
• BRAF wild-type malignant melanoma
• Metastasis to the brain or leptomeninges
• Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics
• Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib
• Current use of a prohibited medication as described in Section 8.9
• History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study
• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
• Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
• Child Pugh B or C liver disease
• Coronary syndromes (including myocardial infarction within 6 months or unstable angina)
• A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of \<50% (see appendix C)
• Treatment refractory hypertension defined as a blood pressure of systolic \>150 mmHg and/or diastolic \>95 mm Hg on \>3 occasions which cannot be controlled by anti-hypertensive therapy
• Uncorrectable electrolyte abnormalities \> CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval

Sponsors & Collaborators

• The Christie NHS Foundation Trust: lead
• University of Manchester: collaborator
• University of Liverpool: collaborator

MeSH Terms

Conditions

Melanoma

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Central Study Contacts

Trial Project Manager

CONTACT

0000; dynamic_study@liverpool.ac.uk

Research Group Project Manager

CONTACT

translationalmelanoma@manchester.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2024
• First Posted: June 24, 2024
• Study Start: June 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: June 24, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share